Novel prostacyclin derivatives and a process for the preparation thereof

Abstract

Compounds of the formula ##STR1## wherein R 1 is (a) hydrogen, (b) C 1-10 alkyl, (c) C 1-10 alkyl substituted by halogen; C 1-4 alkoxy; C 6-10 aryl; C 6-10 aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C 1-4 alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1-4 alkoxy group; di-C 1-4 -alkylamino; or tri-C 1-4 -alkylammonium, (d) C 4-10 cycloalkyl, (e) C 4-10 cycloalkyl substituted by C 1-4 alkyl, (f) C 6-10 aryl, (g) C 6-10 aryl substituted by 1-3 halogen atoms, a phenyl group 1-3 C 1-4 alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1-4 alkoxy group, or (h) an aromatic heterocycle of 5 or 6 ring atoms one of which is O, N or S; A is --CH 2 --CH 2 --, trans--CH═CH-- or --C.tbd.C--; W is hydroxymethylene, RO-methylene, CH 3 or CH 3 , ##STR2## wherein OH or OR is in the α- or β-position and R is an in vivo hydrolyzable and physiologically acceptable ether or acyl group which is conventional for modifying OH groups in prostaglandins; D and E together are a direct bond, or D is C 1-10 alkylene, C 1-10 alkenylene or C 1-10 alkynylene or one of these groups substituted by fluorine, and E is oxygen, --C.tbd.C-- or a direct bond; R 2 is (a) a C 1-10 hydrocarbon aliphatic radical, (b) a C 6-10 hydrocarbon aliphatic radical substituted by C 6-10 aryl or by C 6-10 aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C 1-4 alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1-4 alkoxy group; (c) C 4-10 cycloalkyl, (d) C 4-10 cycloalkyl substituted by C 1-4 alkyl, (e) C 6-10 aryl, (f) C 6-10 aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C 1-4 alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1-4 alkoxy group; or (h) an aromatic heterocycle of 5 or 6 ring atoms one of which is O, N or S; and R 3 is OH or OR; and, when R 1 is hydrogen, the salts thereof with physiologically compatible bases, are effective as antihypertensive, bronchiodilators, thrombocyte aggregation inhibitors, inter alia.

What is claimed is: 
     
       1. A prostane derivative of the formula ##STR16## wherein R 1  is (a) hydrogen, (b) C 1-10  alkyl, (c) C 1-10  alkyl substituted by halogen; C 1-4  alkoxy; C 6-10  aryl; C 6-10  aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C 1-4  alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1-4  alkoxy group; di-C 1-4  -alkylamino; or tri-C 1-4  -alkylammonium; (d) C 4-10  cycloalkyl, (e) C 4-10  cycloalkyl substituted by C 1-4  alkyl, (f) C 6-10  aryl, (g) C 6-10  aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C 1-4  alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1-4  alkoxy group, or (h) an aromatic heterocycle of 5 or 6 ring atoms one of which is O, N or S, the remainder being carbon atoms; A is --CH 2  --CH 2  --, trans--CH═CH-- or --C.tbd.C--;   W is hydroxymethylene, RO-methylene, ##STR17##  wherein OH or OR is in the α- and/or β-position and R is tetrahydropyranyl, tetrahydrofuranyl, α-ethoxyethyl, trimethylsilyl, dimethyl-tert-butylsilyl, tribenzylsilyl or an acyl group of a C 1-15  -hydrocarbon carboxylic or sulfonic acid;   D is C 1-10  alkylene, C 2-10  alkenylene or C 2-10  alkynylene or one of these groups substituted by fluorine, and   E is --C.tbd.C--;   R 2  is (a) a C 1-10  hydrocarbon aliphatic radical, (b) a C 6-10  hydrocarbon aliphatic radical substituted by C 6-10  aryl or by C 6-10  aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C 1-4  alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1-4  alkoxy group; (c) C 4-10  cycloalkyl, (d) C 4-10  cycloalkyl substituted by C 1-4  alkyl, (e) C 6-10  aryl, (f) C 6-10  aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C 1-4  alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C 1-4  alkoxy group; or (h) an aromatic heterocycle of 5 or 6 ring atoms, one of which is O, N or S, the remainder being carbon atoms; and   R 3  is OH or OR; or, when R 1  is hydrogen, a physiologically compatible salt thereof with a base.   
     
     
       2. A compound of claim 1 containing a 16-methyl group. 
     
     
       3. 5-{(E)-(1S,5S,6R,7R)-7-Hydroxy-6-[(E)-3α-hydroxy-oct-1-en-6-inyl]bicyclo[3,3,0]octan-3-ylidene}-pentanoic acid, a compound of claim 1. 
     
     
       4. 5-{(E)-(1S,5S,6R,7R)-7-Hydroxy-6-[(E)-(4RS)-3α-hydroxy-4-methyloct-1-en-6-inyl]bicyclo[3,3,0]-octan-3-ylidene}-pentanoic acid, a compound of claim 1. 
     
     
       5. 5{(E)-(1S,5S,6R,7R)-7-Hydroxy-6-[(E)-3α,β-hydroxy-3-methyloct-1-en-6-inyl]bicyclo[3,3,0]octan-3-ylidene}-pentanoic acid, a compound of claim 1. 
     
     
       6. 5-}(E)-(1S,5S,6R,7R)-7-Hydroxy-6-[(E)-(4RS)-3α-hydroxy-4-methyloct-1-en-6-inyl]bicyclo[3,3,0]octan-3-ylidene}-pentanoic acid methyl ester, a compound of claim 1. 
     
     
       7. 5-{(E)-(1S,5S,6R,7R)-7-Hydroxy-6-[(E)-(4RS)-3α-hydroxy-4-methyloct-1-en-6-inyl]bicyclo[3,3,0]octan-3-ylidene}-pentanoic acid tris(hydroxymethyl)aminomethane salt, a compound of claim 1. 
     
     
       8. A compound of claim 1, wherein R 1  is H. 
     
     
       9. A compound of claim 1, wherein W and R 3  are each OH. 
     
     
       10. A compound of claim 1, wherein R 1  =H, R 3  =OH, A=--trans--C═C--, W=--CHOH--, R 2  =C 1-7  -alkyl, E=--C.tbd.C-- and D=saturated-C 1-10  -alkylene. 
     
     
       11. A compound of claim 10 wherein R 2  =methyl, ethyl, propyl, butyl, isobutyl, t-butyl or pentyl. 
     
     
       12. A compound of claim 10, wherein R 2  =methyl or ethyl. 
     
     
       13. A compound of claim 10, wherein D is straight chained alkylene. 
     
     
       14. A compound of claim 10, wherein D is ethylene. 
     
     
       15. A compound of claim 11, wherein D is ethylene. 
     
     
       16. A compound of claim 12, wherein D is ethylene. 
     
     
       17. A compound of claim 10, wherein D is 1,2-propylene or ethylethylene. 
     
     
       18. A compound of claim 10, wherein D is branched alkylene. 
     
     
       19. A compound of claim 12, wherein D is branched alkylene. 
     
     
       20. A compound of claim 1, wherein A is --CH 2  --CH 2  --. 
     
     
       21. A compound of claim 1, wherein A is --trans--CH═CH--. 
     
     
       22. A compound of claim 1 wherein A is --C═C--, D=saturated --C 1-10  -alkylene, and E is --C.tbd.C--. 
     
     
       23. A compound of claim 22 wherein D is ethylene. 
     
     
       24. A compound of claim 22 wherein R 2  is --C 1-7  -alkyl. 
     
     
       25. A compound of claim 23 wherein R 2  is --C 1-7  -alkyl. 
     
     
       26. A pharmaceutical composition comprising a thrombocyte aggregation inhibiting. 
     
     
       27. A pharmaceutical composition comprising a thrombocyte aggregation inhibiting effective amount of a compound of claim 4 and a pharmaceutically acceptable adjuvant. 
     
     
       28. A pharmaceutical composition comprising a thrombocyte aggregation inhibiting effective amount of a compound of claim 22 and a pharmaceutically acceptable adjuvant. 
     
     
       29. A method of inhibiting thrombocyte aggregation in a patient which comprises administering an effective amount of a compound of claim 1 to the patient. 
     
     
       30. A method of inhibiting thrombocyte aggregation in a patient in need of such treatment comprising administering to the patient an effective amount of a compound of claim 4. 
     
     
       31. A method of inhibiting thrombocyte aggregation in a patient in need of such treatment comprising administering to the patient an effective amount of a compound of claim 22.